CN108451956A - Pharmaceutical composition - Google Patents

Abstract

The present invention relates to the pharmaceutical compositions for including 3 ' H spiral shells of (1r, 4r) 6 ' 4 ', 9 ' dihydro of fluorine N, N 4 phenyl of dimethyl [1,1 ' pyrans of hexamethylene simultaneously [3,4, b] indoles] 4 amine and former times health class.The present invention relates to comprising selected from (1r, 4r) 6' fluorine N, 4 phenyl 4' of N dimethyl, 9' dihydro 3'H spiral shell [hexamethylenes 1,1' pyrans simultaneously [3,4, b] indoles] 4 amine and its acceptable salt of physiology the first pharmacological component and former times health class selected from Meloxicam, piroxicam, tenoxicam, Lornoxicam, Droxicam and its acceptable salt of physiology the second pharmacological component pharmaceutical composition.

Description

pharmaceutical composition

The application date is May 16, 2013, the application number is 201380025679.3, and the invention name is "comprising (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', Invention of the pharmaceutical composition of 9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indol]-4-amine and oxicams" A divisional application of a patent application.

The present invention relates to a compound comprising (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1 , the first pharmacologically active ingredient of 1'-pyrano[3,4,b]indol]-4-amine and its physiologically acceptable salts and selected from the group consisting of meloxicam, piroxicam, tenoxicam, The pharmaceutical composition of the second pharmacologically active ingredient of lornoxicam, droxicam and physiologically acceptable salts of oxicams.

(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyran Do[3,4,b]indol]-4-amine and the corresponding physiologically acceptable salts thereof as well as processes for their preparation are known, eg from WO 2004/043967 and WO 2008/040481. These compounds exhibit analgesic properties and are particularly suitable for the treatment of acute, visceral, neuropathic or chronic (nociceptive) pain.

Oxicams are enolic acids which are preferably considered NSAIDs, ie non-steroidal anti-inflammatory and antirheumatic drugs, which possess anti-inflammatory, analgesic and antipyretic activity.

Although both of the aforementioned classes of substances are useful in the prophylaxis and treatment of pain and are therefore therapeutically effective, side effects may occur, especially with prolonged use or when administered in high doses.

It is further known that certain combinations of pharmacologically active compounds exert superadditive (synergistic) therapeutic effects when administered. An advantage of these special cases is that the total dosage and the risk of unwanted side effects can be reduced accordingly.

On the other hand, two pharmacologically active compounds exerting a synergistic effect can be combined in a single pharmaceutical dosage form, such as a tablet, thereby enhancing patient compliance.

It is an object of the present invention to provide pharmaceutical compositions which have advantages over the pharmaceutical compositions of the prior art. In particular, the pharmaceutical composition should provide rapid efficacy and should also have high tolerance, good compliance and safety.

This object is achieved by the subject-matter of the patent claims.

It has been surprisingly found that a compound containing (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane - The pharmaceutical composition of 1,1'-pyrano[3,4,b]indol]-4-amine and oxicams can be used for the treatment of pain, especially chronic inflammatory pain or acute or non-chronic postoperative pain .

It has also surprisingly been found that said combination exhibits a synergistic therapeutic effect when administered. Thus, the total administered dosage can be reduced so that fewer unwanted side effects occur.

A first aspect of the present invention relates to a pharmaceutical composition comprising:

a) a first pharmacologically active ingredient selected from (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[ Cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine and physiologically acceptable salts thereof, and

b) A second pharmacologically active ingredient which is an oxicam selected from the group consisting of meloxicam, piroxicam, tenoxicam, lornoxicam, droxicam and physiologically acceptable salts thereof.

The pharmaceutical composition of the present invention comprises (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane The first pharmacologically active ingredient of an alkane-1,1'-pyrano[3,4,b]indol]-4-amine and a physiologically acceptable salt thereof.

For the specification, (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1, 1'-pyrano[3,4,b]indol]-4-amine is a compound according to formula (I), which may also be referred to as 1,1-(3-dimethylamino-3-benzene pentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole (trans)

.

The definition of the first pharmacologically active ingredient includes (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro [Cyclohexane-1,1'-pyrano-[3,4,b]indol]-4-amine, i.e. any possible form of the compound according to formula (I), including solvates, co-crystals and polymorphs and their physiologically acceptable salts, especially acid addition salts and corresponding solvates, co-crystals and polymorphs.

Pharmacologically active ingredient (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1' -Pyrano[3,4,b]indol]-4-amine may be present in the pharmaceutical composition of the invention in the form of a physiologically acceptable salt, preferably an acid addition salt, whereby it is possible to use any suitable acid as an addition salt.

(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclo Hexane-1,1'-pyrano[3,4,b]indol]-4-amine is converted into the corresponding addition salt, for example by reaction with a suitable acid. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, and/or aspartame acid. Salt formation is preferably carried out in solvents such as diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. In addition, trimethylchlorosilane in aqueous solution is also suitable for the preparation of the hydrochloride.

In a preferred embodiment, the first pharmacologically active ingredient is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro- 3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine, ie a compound according to formula (I).

In another preferred embodiment, the first pharmacologically active ingredient is a physiologically acceptable acid addition salt, in particular (1r,4r)-6'-fluoro in the form of hydrochloride, hemicitrate or maleate -N,N-Dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole ]-4-amine.

Unless expressly stated otherwise, all amounts of the first pharmacologically active ingredient specified hereinafter are based on the free base form of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', 9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine, i.e. the corresponding amount of the compound according to formula (I) give.

The pharmaceutical composition of the present invention comprises a second pharmacologically active ingredient, which is an oxicam selected from the group consisting of meloxicam, piroxicam, tenoxicam, lornoxicam, droxicam and physiologically acceptable salts thereof .

Meloxicam, piroxicam, tenoxicam, lornoxicam and droxicam are compounds according to formulas (II), (III), (IV), (V) and (VI), respectively.

The definition of second pharmacologically active ingredient includes any possible form of the above-mentioned oxicams, including any enantiomers (if applicable), solvates, prodrugs, co-crystals and polymorphs and their physiologically acceptable salts, especially the metal and ammonium salts and the corresponding solvates, co-crystals and polymorphs.

Although preferred oxicams according to any of formulas (II) to (VI) do not themselves contain acid functional groups, they bear acidic protons because they exhibit keto-enol tautomerism. Additionally, they may contain nitrogen functional groups. Salts can thus be converted in a manner known to those skilled in the art, for example by reaction with suitable bases and with acids or metal salts. Suitable bases include, but are not limited to, inorganic bases, including hydroxides of sodium, potassium, calcium and/or magnesium, and organic bases, such as triethylamine, trimethylamine, N,N-diisopropylethylamine, N -Methylmorpholine, N-methylpiperidine and ammonia. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, and/or aspartame acid. In addition, trimethylchlorosilane in aqueous solution is also suitable for the preparation of the hydrochloride. Suitable metal salts include, but are not limited to, alkali metal salts such as sodium, potassium or lithium phosphates, sulfates, methanesulfonates, formates, acetates, oxalates, succinates, tartrates, almonds salts, fumarates, lactates, citrates, glutamate, aspartate and/or silyl salts, and alkaline earth metal salts, especially magnesium and calcium salts, including their phosphoric acid Salt, sulfate, methanesulfonate, formate, acetate, oxalate, succinate, tartrate, mandelate, fumarate, lactate, citrate, glutamate , aspartate and/or silyl salts. Salt formation is preferably carried out in solvents such as diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.

Ethers and esters are especially preferred as prodrugs of the preferred oxicams according to any of formulas (II) to (VI). For example in "Textbook of Drug Design and Discovery", 3rd edition, 2002, Chapter 14, pp. 410-458, editors: Krogsgaard-Larsen et al., Taylor & Francis describe suitable methods for selecting and preparing a given substance. Prodrug method.

The second pharmacologically active ingredient is an oxicam selected from the group consisting of meloxicam, piroxicam, tenoxicam, lornoxicam, droxicam and physiologically acceptable salts thereof.

In a preferred embodiment, the second pharmacologically active ingredient is an oxicam selected from the group consisting of meloxicam, piroxicam, tenoxicam and lornoxicam and their physiologically acceptable salts.

Unless expressly stated otherwise, all amounts specified hereinafter for the second pharmacologically active ingredient are given in terms of the free compound, ie the corresponding amount of the compound according to any of formulas (II) to (VI).

In a preferred embodiment, the second pharmacologically active ingredient is in free compound form, ie an oxicam according to any of formulas (II) to (VI).

In another preferred embodiment, the second pharmacologically active ingredient is selected from the group consisting of meloxicam, piroxicam, tenoxicam and lornoxicam according to any of the formulas (II) to (V) in free compound form. Kang's Oxicam class.

In yet another preferred embodiment, the second pharmacologically active ingredient is an oxicam selected from the group consisting of meloxicam, piroxicam, tenoxicam and lornoxicam in their respective sodium salt forms.

In a preferred embodiment, the second pharmacologically active ingredient is meloxicam.

In a preferred embodiment, the first pharmacologically active ingredient is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro- 3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine, i.e. a compound according to formula (I), and the second pharmacologically active ingredient is according to Oxicams of any of formulas (II) to (VI).

In another preferred embodiment, the first pharmacologically active ingredient is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro -3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine, i.e. a compound according to formula (I), and the second pharmacologically active ingredient is Oxicams selected from the group consisting of meloxicam, piroxicam, tenoxicam and lornoxicam according to any of formulas (II) to (V).

In yet another preferred embodiment, the first pharmacologically active ingredient is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro -3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine, i.e. a compound according to formula (I), and the second pharmacologically active ingredient is Oxicams selected from the group consisting of meloxicam, piroxicam, tenoxicam and lornoxicam in their respective sodium salt forms.

In yet another preferred embodiment, the first pharmacologically active ingredient is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro in free base form -3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine, i.e. a compound according to formula (I), and the second pharmacologically active ingredient is Meloxicam according to formula (II).

In another preferred embodiment, the first pharmacologically active ingredient is a physiologically acceptable acid addition salt, in particular (1r,4r)-6'-fluoro in the form of hydrochloride, hemicitrate or maleate -N,N-Dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole ]-4-amine, and the second pharmacologically active ingredient is meloxicam according to formula (II).

In a further preferred embodiment, the first pharmacologically active ingredient is a physiologically acceptable acid addition salt, in particular (1r,4r)-6'-fluoro in the form of hydrochloride, hemicitrate or maleate -N,N-Dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole ]-4-amine, and the second pharmacologically active ingredient is meloxicam in the form of sodium salt.

Since the second pharmacologically active ingredient bears an acidic proton due to keto-enol tautomerization, it may react with the first pharmacologically active ingredient according to formula (I) to form a salt comprising both pharmacologically active ingredients.

Therefore, in another preferred embodiment, the pharmaceutical composition according to the invention comprises the first and the second pharmacologically active ingredient in the form of a salt formed from these two pharmacologically active ingredients. This salification may be partial, ie the pharmaceutical compositions according to the invention also comprise one or both of these pharmacologically active ingredients in their non-salt form, or this salification may be substantially complete.

Another aspect of the invention relates to pharmaceutical dosage forms comprising the pharmaceutical composition of the invention.

The first and second pharmacologically active ingredients are generally contained in the pharmaceutical dosage forms of the invention in therapeutically effective amounts. The amount that constitutes a therapeutically effective amount will vary with the pharmacologically active ingredient, the condition being treated, the severity of the condition, the patient being treated and whether the pharmaceutical dosage form is designed for immediate or controlled release.

In a preferred embodiment, the content of the first pharmacologically active ingredient in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention is at most 10% by weight or at most 5% by weight or at most 3% by weight or at most 1.0% by weight, More preferably at most 0.8% by weight, still more preferably at most 0.5% by weight, still more preferably at most 0.2% by weight, still more preferably at most 0.1% by weight, most preferably at most 0.05% by weight, especially at most 0.01% by weight or at most 0.005% by weight or Up to 0.001% by weight.

In a preferred embodiment, the content of the second pharmacologically active ingredient in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention is at most 95% by weight, more preferably at most 80% by weight, even more preferably at most 70% by weight, Even more preferably at most 60% by weight, even more preferably at most 55% by weight, most preferably at most 50% by weight, especially at most 45% by weight.

In another preferred embodiment, the content of the second pharmacologically active ingredient in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention is at most 45% by weight, more preferably at most 30% by weight, even more preferably at most 20% by weight , still more preferably at most 15% by weight, even more preferably at most 10% by weight, most preferably at most 5% by weight, especially at most 1% by weight.

In a preferred embodiment, the content of the first pharmacologically active ingredient in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention is at least 0.0001% by weight, more preferably at least 0.0003% by weight, even more preferably at least 0.0005% by weight, Even more preferably at least 0.0008% by weight, even more preferably at least 0.001% by weight, most preferably at least 0.003% by weight, especially at least 0.005% by weight.

In a preferred embodiment, the content of the second pharmacologically active ingredient in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention is at least 0.1% by weight, more preferably at least 0.5% by weight, even more preferably at least 1% by weight, Even more preferably at least 3% by weight, even more preferably at least 5% by weight, most preferably at least 7.5% by weight, especially at least 10% by weight.

In another preferred embodiment, the content of the second pharmacologically active ingredient in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention is at least 0.01% by weight, more preferably at least 0.02% by weight, even more preferably at least 0.04% by weight , still more preferably at least 0.06% by weight, most preferably at least 0.08% by weight, especially at least 0.1% by weight.

Unless expressly specified otherwise, within the meaning of the present invention, the notation "% by weight" shall refer to the weight of each ingredient/total weight of the pharmaceutical dosage form or the weight of each ingredient/total weight of the pharmaceutical composition.

Preferably, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is in the range of 1: 2 to 1: 1,000,000, more preferably 1: 2 to 1 : 10,000, most preferably in the range of 1 : 5 to 1 : 5,000.

In a preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 2 and 1: 100, more preferably 1 :4 to 1:90, still more preferably 1:6 to 1:80, most preferably 1:7 to 1:70, especially in the range of 1:10 to 1:60.

In another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is 1: 20 to 1: 200, more preferably 1:30 to 1:185, more preferably 1:50 to 1:170, even more preferably 1:60 to 1:160, most preferably 1:70 to 1:140, especially 1:80 to 1:120 within range.

In yet another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 100 and 1: 900, more preferably 1:250 to 1:800, more preferably 1:300 to 1:700, most preferably 1:350 to 1:650, especially 1:400 to 1:600.

In yet another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 500 and 1: 5,000, more preferably 1:600 to 1:4,000, still more preferably 1:700 to 1:3,000, most preferably 1:750 to 1:2,500, especially 1:800 to 1:2,000.

In another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is 1: 1,000 to 1: 9,000, more preferably 1:2,500 to 1:8,000, still more preferably 1:3,000 to 1:7,000, most preferably 1:3,500 to 1:6,500, especially 1:4,000 to 1:6,000.

In yet another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is 1: 3,000 to 1: 10,000, more preferably 1:4,000 to 1:9,800, still more preferably 1:5,000 to 1:9,600, most preferably 1:6,000 to 1:9,500, especially 1:7,000 to 1:9,000.

Preferably, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is in the range of 1: 2 to 1: 1,000,000, more preferably 1: 2 to 1 : 10,000, most preferably in the range of 1 : 5 to 1 : 5,000.

In a preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 2 and 1: 100, more preferably 1 :4 to 1:90, still more preferably 1:6 to 1:80, most preferably 1:7 to 1:70, especially in the range of 1:10 to 1:60.

In another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 20 and 1: 200, more preferably 1:30 to 1:185, more preferably 1:50 to 1:170, even more preferably 1:60 to 1:160, most preferably 1:70 to 1:140, especially 1:80 to 1:120 within range.

In yet another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 100 and 1: 900, more preferably 1:250 to 1:800, more preferably 1:300 to 1:700, most preferably 1:350 to 1:650, especially 1:400 to 1:600.

In yet another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 500 and 1: 5,000, more preferably 1:600 to 1:4,000, still more preferably 1:700 to 1:3,000, most preferably 1:750 to 1:2,500, especially 1:800 to 1:2,000.

In another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is 1: 1,000 to 1: 9,000, more preferably 1:2,500 to 1:8,000, still more preferably 1:3,000 to 1:7,000, most preferably 1:3,500 to 1:6,500, especially 1:4,000 to 1:6,000.

In yet another preferred embodiment, in the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is between 1: 3,000 and 1: 10,000, more preferably 1:4,000 to 1:9,800, still more preferably 1:5,000 to 1:9,600, most preferably 1:6,000 to 1:9,500, especially 1:7,000 to 1:9,000.

The amount of the first and second pharmacologically active ingredients contained in the pharmaceutical dosage form of the present invention may vary with various factors well known to those skilled in the art, for example, patient weight, route of administration, disease severity, and the like.

In general, both pharmacologically active ingredients contained in the pharmaceutical dosage forms according to the invention are administered in amounts up to their maximum daily doses known to those skilled in the art. For example, as the second pharmacologically active ingredient, meloxicam is preferably administered to the patient at a maximum daily dose of 15 mg, piroxicam is preferably administered to the patient at a maximum daily dose of 40 mg, tenoxicam is preferably administered at a maximum A maximum daily dose of 40 mg is administered to the patient, and lornoxicam is preferably administered to the patient at a maximum daily dose of up to 16 mg.

When administered in an indicated manner, for example once a day or twice a day, the pharmaceutical dosage form of the present invention and the pharmaceutical composition of the present invention respectively preferably contain a respective maximum amount of the first and second pharmacologically active ingredients independently of each other. 75±15% by weight, 75±10% by weight, 75±5% by weight, 50±15% by weight, 50±10% by weight, 50±5% by weight, 25±15% by weight, 25±10% by weight of the daily dose Or the first and second pharmacologically active ingredients in an amount of 25±5% by weight.

Preferably, the pharmaceutical dosage form of the present invention is contained in an amount of 0.1 μg to 5,000 μg, more preferably 0.1 μg to 2,500 μg, even more preferably 1.0 μg to 1,000 μg, still more preferably 10 to 800 μg, most preferably 15 μg to 600 μg, especially Doses ranging from 20 micrograms to 440 micrograms contain the first pharmacologically active ingredient.

In a preferred embodiment, the pharmaceutical dosage form of the present invention is at 13 ± 12 micrograms, more preferably 13 ± 10 micrograms, even more preferably 13 ± 8 micrograms, even more preferably 13 ± 6 micrograms, even more preferably 13 ± 5 micrograms, Most preferably a dose in the range of 13±4 micrograms, especially 13±3 micrograms contains the first pharmacologically active ingredient.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is contained in an amount of 20 ± 15 micrograms, more preferably 20 ± 13 micrograms, even more preferably 20 ± 12 micrograms, even more preferably 20 ± 10 micrograms, even more preferably 20 ± 8 micrograms , most preferably a dose within the range of 20±6 micrograms, especially 20±5 micrograms, contains the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is obtained at 40 ± 35 micrograms, more preferably 40 ± 30 micrograms, even more preferably 40 ± 25 micrograms, even more preferably 40 ± 20 micrograms, even more preferably 40 ± 15 micrograms , most preferably a dose within the range of 40±10 micrograms, especially 40±5 micrograms, contains the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is at 60 ± 50 micrograms, more preferably 60 ± 40 micrograms, even more preferably 60 ± 30 micrograms, even more preferably 60 ± 20 micrograms, most preferably 60 ± 10 micrograms, In particular doses in the range of 60±5 micrograms contain the first pharmacologically active ingredient.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is contained in an amount of 80 ± 70 micrograms, more preferably 80 ± 60 micrograms, even more preferably 80 ± 50 micrograms, even more preferably 80 ± 40 micrograms, even more preferably 80 ± 20 micrograms , most preferably a dose within the range of 80±10 micrograms, especially 80±5 micrograms, contains the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is contained in an amount of 100±90 micrograms, more preferably 100±80 micrograms, even more preferably 100±60 micrograms, even more preferably 100±40 micrograms, and even more preferably 100±20 micrograms , most preferably in the range of 100±10 micrograms, especially 100±5 micrograms, containing the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention has a dosage of 120 ± 100 micrograms, more preferably 120 ± 80 micrograms, even more preferably 120 ± 60 micrograms, even more preferably 120 ± 40 micrograms, even more preferably 120 ± 20 micrograms , most preferably in a dose within the range of 120±10 micrograms, especially 120±5 micrograms, containing the first pharmacologically active ingredient.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is dosed at 150±90 micrograms, more preferably 150±80 micrograms, even more preferably 150±60 micrograms, even more preferably 150±40 micrograms, even more preferably 150±20 micrograms , most preferably in a dose within the range of 150±10 micrograms, especially 150±5 micrograms, containing the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention has a dosage of 170 ± 130 micrograms, more preferably 170 ± 100 micrograms, even more preferably 170 ± 80 micrograms, even more preferably 170 ± 60 micrograms, even more preferably 170 ± 40 micrograms , most preferably a dosage within the range of 170±20 micrograms, especially 170±10 micrograms, contains the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is contained in an amount of 200±175 micrograms, more preferably 200±150 micrograms, even more preferably 200±125 micrograms, even more preferably 200±100 micrograms, even more preferably 200±75 micrograms , most preferably in the range of 200±50 micrograms, especially 200±25 micrograms, containing the first pharmacologically active ingredient.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is contained in a concentration of 400±350 micrograms, more preferably 400±300 micrograms, even more preferably 400±250 micrograms, even more preferably 400±200 micrograms, and even more preferably 400±150 micrograms , most preferably in the range of 400±100 micrograms, especially 400±50 micrograms, containing the first pharmacologically active ingredient.

In another preferred embodiment, the dosage of the pharmaceutical dosage form of the present invention is 600 ± 400 micrograms, more preferably 600 ± 300 micrograms, even more preferably 600 ± 250 micrograms, even more preferably 600 ± 200 micrograms, even more preferably 600 ± 150 micrograms , most preferably in the range of 600±100 micrograms, especially 600±50 micrograms, containing the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is contained in an amount of 800±550 micrograms, more preferably 800±400 micrograms, even more preferably 800±350 micrograms, even more preferably 800±250 micrograms, even more preferably 800±150 micrograms , most preferably a dose in the range of 800±100 micrograms, especially 800±50 micrograms, contains the first pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is dosed at 1,000±800 micrograms, more preferably 1,000±600 micrograms, still more preferably 1,000±500 micrograms, still more preferably 1,000±300 micrograms, still more preferably 1,000±200 micrograms , most preferably a dose in the range of 1,000±100 micrograms, especially 1,000±50 micrograms contains the first pharmacologically active ingredient.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is contained in a concentration of 1,200±1,000 micrograms, more preferably 1,200±800 micrograms, still more preferably 1,200±600 micrograms, still more preferably 1,200±400 micrograms, and even more preferably 1,200±200 micrograms , most preferably a dose in the range of 1,200±100 micrograms, especially 1,200±50 micrograms contains the first pharmacologically active ingredient.

Preferably, the pharmaceutical dosage form of the present invention contains Second pharmacologically active ingredient.

In a preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose in the range of 10±8 mg, more preferably 10±6 mg, most preferably 10±4 mg, especially 10±2 mg.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is in the range of 15 ± 10 mg, more preferably 15 ± 8 mg, even more preferably 15 ± 6 mg, most preferably 15 ± 4 mg, especially 15 ± 2 mg. The dosage contains the second pharmacologically active ingredient.

In yet another preferred embodiment, the dosage form of the present invention is 20 ± 15 mg, more preferably 20 ± 14 mg, even more preferably 20 ± 12 mg, even more preferably 20 ± 10 mg, most preferably 20 ± 8 mg, In particular dosages in the range of 20±5 mg contain the second pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is at 25 ± 15 mg, more preferably 25 ± 14 mg, even more preferably 25 ± 13 mg, even more preferably 25 ± 12 mg, most preferably 25 ± 10 mg, In particular doses in the range of 25±7 mg contain the second pharmacologically active ingredient.

In another preferred embodiment, the dosage form of the present invention is 30 ± 20 mg, more preferably 30 ± 18 mg, even more preferably 30 ± 15 mg, even more preferably 30 ± 13 mg, most preferably 30 ± 10 mg, In particular dosages in the range of 30±8 mg contain the second pharmacologically active ingredient.

In another preferred embodiment, the dosage form of the present invention is 35 ± 20 mg, more preferably 35 ± 18 mg, even more preferably 35 ± 15 mg, even more preferably 35 ± 13 mg, most preferably 35 ± 10 mg, In particular doses in the range of 35±8 mg contain the second pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is at 40 ± 20 mg, more preferably 40 ± 18 mg, even more preferably 40 ± 15 mg, even more preferably 40 ± 13 mg, most preferably 40 ± 10 mg, In particular dosages in the range of 40±8 mg contain the second pharmacologically active ingredient.

In a preferred embodiment, the pharmaceutical dosage form is in the range of 2 mg to 28 mg, more preferably in the range of 4 mg to 26 mg, still more preferably in the range of 5 mg to 24 mg, still more preferably in the range of 6 mg to Doses in the range of 22 mg, most preferably in the range of 7 mg to 20 mg, especially in the range of 8 mg to 18 mg contain meloxicam as the second pharmacologically active ingredient.

In another preferred embodiment, the pharmaceutical dosage form is in the range of 5 mg to 50 mg, more preferably in the range of 7 mg to 45 mg, still more preferably in the range of 9 mg to 40 mg, still more preferably in the range of 12 mg Dosages in the range of up to 35 mg, most preferably in the range of 13 mg to 30 mg, especially in the range of 15 mg to 25 mg contain piroxicam as the second pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form is in the range of 5 mg to 50 mg, more preferably in the range of 7 mg to 45 mg, still more preferably in the range of 9 mg to 40 mg, still more preferably in the range of 12 mg Dosages in the range of up to 35 mg, most preferably in the range of 13 mg to 30 mg, especially in the range of 15 mg to 25 mg contain tenoxicam as the second pharmacologically active ingredient.

In yet another preferred embodiment, the pharmaceutical dosage form is in the range of 2 mg to 26 mg, more preferably in the range of 4 mg to 24 mg, still more preferably in the range of 5 mg to 22 mg, still more preferably in the range of 6 mg Dosages in the range of up to 20 mg, most preferably in the range of 7 mg to 18 mg, especially in the range of 8 mg to 16 mg contain lornoxicam as the second pharmacologically active ingredient.

In the pharmaceutical dosage form of the present invention, the dose of the first pharmacologically active ingredient is preferably in the range of 1:20 to 20:1 of the amount equivalent to the dose of the second pharmacologically active ingredient. "Equivalent" in this regard preferably refers to the dose required to achieve an equivalent desired therapeutic effect when administered alone. The skilled artisan will recognize that when the desired therapeutic effect is an analgesic effect, equivalent doses are determined for the analgesic properties of the first pharmacologically active ingredient and the second pharmacologically active ingredient.

For example, when the dose of the second pharmacologically active ingredient contained in the pharmaceutical dosage form of the present invention is, for example, 30 mg in total and provides an analgesic effect E when administered alone at this dose and when the equivalent amount of the first pharmacologically active ingredient ( That is, when the amount required to provide the same analgesic effect (E) when administered alone is, for example, 4 micrograms, the dose of the first pharmacologically active ingredient contained in the pharmaceutical dosage form of the present invention can be 0.2 micrograms (4 micrograms/20) to 80 Micrograms (20.4 micrograms) range.

In a preferred embodiment, the dosage of the first pharmacologically active ingredient is in the range of 1:15 to 15:1, preferably in the range of 1:10 to 10:1, of an amount equivalent to the dosage of the second pharmacologically active ingredient , more preferably in the range of 1:8 to 8:1, still more preferably in the range of 1:6 to 6:1, still more preferably in the range of 1:4 to 4:1, most preferably in the range of 1 : in the range of 3 to 3: 1, particularly preferably in the range of 1: 2 to 2: 1.

Suitable routes of administration for the pharmaceutical dosage forms of the present invention include, but are not limited to, oral, intravenous, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, topical and/or rectal administration .

In a preferred embodiment, the pharmaceutical dosage form according to the invention is for oral administration.

In another preferred embodiment, the pharmaceutical dosage forms according to the invention are intended for parenteral, in particular intravenous, intraperitoneal, intrathecal, intramuscular or subcutaneous administration.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is for rectal administration.

The pharmaceutical dosage form of the invention and the pharmaceutical composition of the invention may be solid, semi-solid or liquid, respectively.

The pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention respectively may contain auxiliary agents such as carriers, fillers, solvents, diluents, colorants and/or binders. The choice of the adjuvants used and their amounts depends, for example, on how the first and second pharmacologically active ingredients are to be administered, e.g. orally, intravenously, intraperitoneally, intradermally, transdermally, intrathecally, intramuscularly, intranasally, transmucosally, Subcutaneously, rectally or topically.

Suitable auxiliaries are in particular any substances known to the person skilled in the art to be useful in the preparation of galenical forms. Examples of suitable adjuvants include, but are not limited to: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, Starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone , paraffin, wax, natural and synthetic gums, acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, lauryl Sodium hydroxysulfate, edible oil, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and polypropylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbic acid, Tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, hydrogen phosphate Calcium, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.

Pharmaceutical dosage forms suitable for oral administration include, but are not limited to, tablets, effervescent tablets, chewable tablets, dragees, capsules, drops, juices, and syrups. Oral pharmaceutical dosage forms may also be in multiparticulate form, such as granules, pills, spheres, crystals, etc., optionally compressed into tablets, capsules, sachets or suspended in a suitable liquid medium. Oral dosage forms can also be provided with enteric coatings.

Pharmaceutical dosage forms suitable for parenteral, topical and inhalational administration include, but are not limited to, solutions, suspensions, easily reconstitutable dry formulations and sprays.

Suppositories are pharmaceutical dosage forms suitable for rectal administration. Dosage forms as a deposit (in dissolved form), for example as a patch, optionally with the addition of a skin penetration enhancer, are examples of dosage forms suitable for transdermal administration.

In an especially preferred embodiment, the pharmaceutical dosage form according to the invention is a tablet.

In a preferred embodiment, the pharmaceutical dosage form according to the invention is administered six times a day, five times a day, four times a day, three times a day, twice a day, once a day or less frequently.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is suitable for administration less than once a day, preferably three times four days (3/4), two times three days (2/3), three times five days (3 /5), once every two days (1/2), three times a week (3/7), twice every five days (2/5), once every three days (1/3), twice a week (2/7), four times a week Once a day (1/4), once every five days (1/5), once every six days (1/6), or once a week (1/7). According to this embodiment, once-daily dosing (1/2) is particularly preferred.

In a preferred embodiment, especially when the second pharmacologically active ingredient is meloxicam, piroxicam or tenoxicam, the pharmaceutical dosage form according to the invention is administered less frequently than once a day, in particular two days Once (1/2).

In another preferred embodiment, the pharmaceutical dosage form according to the invention is administered once a day.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is administered twice daily.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is administered three times a day.

In another preferred embodiment, especially when the second pharmacologically active ingredient is meloxicam or lornoxicam, the pharmaceutical dosage form according to the invention is administered several times a day, in particular twice a day.

For the purposes of the description, "dosing three times a day" (tid) preferably means that the pharmaceutical dosage form of the invention is suitable for sequential administration according to a regimen comprising daily administration of three pharmaceutical dosage forms, wherein between successive administrations of two pharmaceutical dosage forms The time interval is at least 3 hours, preferably at least 4 hours, more preferably at least 6 hours, especially about 8 hours.

For the purposes of the description, "dosing twice a day" (bid) preferably means that the pharmaceutical dosage form of the invention is suitable for sequential administration according to a regimen comprising daily administration of two pharmaceutical dosage forms, wherein the sequential administration of the two pharmaceutical dosage forms The time interval between is at least 6 hours, preferably at least 8 hours, more preferably at least 10 hours, especially about 12 hours.

For the purposes of the description, "once-daily administration" (sid) preferably means that the pharmaceutical dosage forms of the present invention are suitable for sequential administration according to a regimen comprising daily administration of one pharmaceutical dosage form, wherein the period between successive administrations of the two pharmaceutical dosage forms is The time interval is at least 18 hours, preferably at least 20 hours, more preferably at least 22 hours, especially about 24 hours.

The skilled person is well aware that the above-mentioned dosing regimen can be achieved by administering a single pharmaceutical dosage form containing the complete amount of the first pharmacologically active ingredient and the complete amount of the second pharmacologically active ingredient to be administered at a specific point in time, or by administering multiple doses unit, i.e. two, three or more dosage units which together contain the complete amounts of the first pharmacologically active ingredient and the second pharmacologically active ingredient to be administered at the specified point in time, wherein each dosage Units are suitable for administration at the same time or within a short period of time, for example within 5, 10 or 15 minutes.

Hereinafter, the doses of the first and second pharmacologically active ingredients are expressed in terms of the number of daily prescribed administrations "n", ie the number of administrations of the pharmaceutical dosage form according to the invention during a 24-hour period. For example, 100/n µg is equivalent to a dose of 100 micrograms given once daily (n = 1), and 100/n µg is equivalent to 50 micrograms given twice daily (n = 2) dosage.

In a preferred embodiment, the pharmaceutical dosage form of the invention is administered less frequently (n=1/2, 3/5 or 2/3) than once daily, wherein the pharmaceutical dosage form contains 15/n to 100/n µg, preferably a dose of 20/n to 80/n µg of the first pharmacologically active ingredient and a dose of 2/n to 50/n mg of the second pharmacologically active ingredient. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in tablet form.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is administered once a day (n=1), wherein the pharmaceutical dosage form contains 15/n to 100/n µg, preferably 20/n to 80/n µg of The first pharmacologically active ingredient and the second pharmacologically active ingredient at a dose of 2/n to 50/n mg. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in tablet form.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is administered multiple times a day (n=2, 3, 4, 5 or 6), wherein the pharmaceutical dosage form contains 15/n to 100/n µg, preferably 20/n A dose of n to 80/n µg of the first pharmacologically active ingredient and a dose of 2/n to 50/n mg of the second pharmacologically active ingredient. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in tablet form.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is administered less frequently (n=1/2, 3/5 or 2/3) than once daily, wherein the pharmaceutical dosage form contains 150/n to 1,200/ n µg, preferably a dose of 200/n to 800/n µg of the first pharmacologically active ingredient and a dose of 2/n to 50/n mg of the second pharmacologically active ingredient. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in tablet form.

In another preferred embodiment, the pharmaceutical dosage form of the present invention is administered once a day (n=1), wherein the pharmaceutical dosage form contains 150/n to 1,200/n µg, preferably 200/n to 800/n µg of The first pharmacologically active ingredient and the second pharmacologically active ingredient at a dose of 2/n to 50/n mg. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in tablet form.

In yet another preferred embodiment, the pharmaceutical dosage form of the present invention is administered multiple times a day (n=2, 3, 4, 5 or 6), wherein the pharmaceutical dosage form contains 150/n to 1,000/n µg, preferably 200/n A dose of n to 800/n µg of the first pharmacologically active ingredient and a dose of 2/n to 50/n mg of the second pharmacologically active ingredient. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in tablet form.

The pharmaceutical dosage form of the present invention may provide immediate or controlled release of the first pharmacologically active ingredient and/or the second pharmacologically active ingredient under in vitro conditions. The in vitro release is preferably determined according to Ph. Eur., preferably using the paddle method with a sinker, 75 rpm, 37° C., 900 ml artificial gastric juice, pH 6.8.

The first pharmacologically active ingredient and/or the second pharmacologically active ingredient can be present independently of one another at least partially in controlled-release form in the pharmaceutical dosage form. For example, the first pharmacologically active ingredient and/or the second pharmacologically active ingredient may be released from the pharmaceutical dosage form in a prolonged manner, eg if administered orally, rectally or transdermally. Such pharmaceutical dosage forms are particularly useful for "once-daily" or "twice-daily" formulations, which need only be taken once a day or twice a day, respectively. Suitable release-controlling materials are well known to those skilled in the art.

The pharmaceutical dosage form of the invention providing controlled release of the first pharmacologically active ingredient and/or the second pharmacologically active ingredient may be manufactured using materials, means, devices and methods well known in the art of pharmaceutical dosage forms.

In order to obtain solid pharmaceutical dosage forms, such as tablets, for example, the pharmacologically active ingredients of the pharmaceutical composition can be mixed with pharmaceutical carriers, such as traditional tablet ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, Dibasic calcium phosphate, or pharmaceutically acceptable gum, is granulated with a pharmaceutical diluent, such as water, to form a solid composition containing a uniform distribution of the pharmacologically active ingredient. The term "uniform distribution" is intended to mean that the pharmacologically active ingredient is evenly distributed throughout the composition so that the composition can be easily divided into equivalent dosage units such as tablets, pills or capsules and the like. The solid composition is then divided into dosage units. Tablets or pills of the pharmaceutical composition of the invention may also be coated or compounded in various ways to provide a controlled release dosage form.

If one of the pharmacologically active ingredients is to be released before the other, eg at least 30 minutes or 1 hour earlier, a pharmaceutical dosage form can be prepared with a corresponding release profile. An example of such a pharmaceutical dosage form is an osmotically driven release system for achieving a delayed release of the first or second pharmacologically active ingredient from the interior (core) of the pharmaceutical dosage form via a coating which itself contains a correspondingly earlier release of another pharmacologically active ingredient. A pharmacologically active ingredient. In such release systems which are particularly suitable for oral administration, at least a part of the release system, preferably the entire surface, preferably those parts which will be in contact with the release medium, is semipermeable, preferably with a semipermeable coating, so that the surface is The release medium is permeable, but substantially, preferably completely impermeable to the pharmacologically active ingredient contained in the core, the surface and/or optionally the coating comprising at least one opening for releasing the pharmacologically active ingredient contained in the core. Furthermore, that/those surfaces which come into contact with the release medium are precisely provided with a coating which contains and releases another pharmacologically active ingredient. This is preferably intended to mean a system in the form of a tablet comprising a release port, a core containing the first or second pharmacologically active ingredient, a polymer portion which exerts pressure upon swelling, a semipermeable membrane and a coating containing the other pharmacologically active ingredient . Embodiments and examples of osmotically driven release systems are disclosed, for example, in US Patent Nos. 4,765,989, 4,783,337, and 4,612,008.

Another example of a suitable pharmaceutical dosage form is a gel-matrix tablet. Suitable examples are provided in US Patents 4,389,393, 5,330,761, 5,399,362, 5,472,711 and 5,455,046. Particularly suitable are sustained-release matrix dosage forms with a non-uniform distribution of the pharmaceutical composition, whereby, for example, one pharmacologically active ingredient, i.e. the first or second pharmacologically active ingredient, is distributed in the outer region of the matrix (fastest with release medium In the contact part), another pharmacologically active ingredient is distributed inside the matrix. Upon contact with the release medium, the outer matrix layer initially (and rapidly) swells and first releases the pharmacologically active ingredient contained therein, followed by a significantly (more) controlled release of the other pharmacologically active ingredient. Examples of suitable matrices include matrices comprising 1 to 80% by weight of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix formers.

Preferably, the pharmaceutical dosage form according to the invention provides immediate release of the first pharmacologically active ingredient and immediate or controlled release of the second pharmacologically active ingredient.

In a preferred embodiment, the pharmaceutical dosage form according to the invention provides immediate release of the first and second pharmacologically active ingredients.

In another preferred embodiment, the pharmaceutical dosage form according to the invention provides immediate release of the first pharmacologically active ingredient and controlled release of the second pharmacologically active ingredient. This release profile can be achieved using the methods described above, such as an osmotically driven release system providing the first pharmacologically active ingredient in the coating and the second pharmacologically active ingredient in the core or having the first pharmacologically active ingredient in the outer matrix layer and the matrix in the matrix. A sustained-release matrix dosage form containing a second pharmacologically active ingredient inside.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention provides controlled release of the first and second pharmacologically active ingredients.

In another aspect, the present invention relates to the use of the pharmaceutical composition of the present invention and the pharmaceutical dosage form of the present invention in the prevention or treatment of pain, respectively.

In a preferred embodiment, the pharmaceutical composition of the present invention and the pharmaceutical dosage form of the present invention are respectively used for the treatment of pain, wherein the pain is preferably

- Peripheral, central, or musculoskeletal pain; and/or

- Acute, subacute or chronic pain; and/or

- Moderate to severe pain; and/or

- neuropathic or psychiatric or nociceptive or mixed pain; and/or

- low back pain, visceral pain or headache; and/or

- Postoperative pain, cancer pain or inflammatory pain.

For purposes of the specification, "acute pain" preferably refers to pain that lasts up to about 4 weeks, "subacute pain" preferably refers to pain that lasts for more than about 4 weeks to about 12 weeks, and "chronic pain" preferably refers to pain that lasts for more than About 12 weeks of pain.

The pain is preferably selected from cancer pain, peripheral neuropathic pain, osteoarthritis, chronic visceral pain, neuropathic pain (diabetic polyneuropathy, HIV-associated neuropathic pain, post-traumatic neuropathic pain, postherpetic neuralgia, chemotherapy-related pain), postzosteric neuralgia, postoperative neuropathic pain, inflammatory pain, migraine, low back pain, fibromyalgia, and trigeminal neuralgia.

In a preferred embodiment, the pain is chronic pain, in particular chronic nociceptive pain and/or chronic inflammatory pain.

In another preferred embodiment, the pain is non-chronic or acute pain, especially postoperative pain.

In yet another preferred embodiment, the pain is selected from acute or non-chronic postoperative neuropathic pain and chronic inflammatory pain.

Hereinafter, the doses of the first and second pharmacologically active ingredients are still expressed in terms of the daily number of administrations "n", ie the number of administrations of the pharmaceutical dosage form according to the invention during a 24-hour period.

In a preferred embodiment, the pharmaceutical dosage form is used for the treatment of neuropathic pain, which may optionally be superimposed on nociceptive pain, wherein the dosage of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 1/n µg to 800/ n µg or 1/n µg to 600/n µg or 1/n µg to 400/n µg or 1/n µg to 250/n µg, more preferably 5/n µg to 150/n µg, even more preferably 10/n µg n µg to 100/n µg, most preferably 20/n µg to 80/n µg, especially 30/n µg to 50/n µg. According to this embodiment, the dosage of the second pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 2/n mg to 50/n mg.

In a preferred embodiment, especially when the pharmaceutical dosage form is used for the treatment of neuropathic pain and the second pharmacologically active ingredient is meloxicam, the dose of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 1/ n µg to 800/n µg or 1/n µg to 600/n µg or 1/n µg to 400/n µg or 1/n µg to 250/n µg, more preferably 5/n µg to 150/n µg, Still more preferably 10/n µg to 100/n µg, most preferably 20/n µg to 80/n µg, especially 30/n µg to 50/n µg; and the second pharmacologically active ingredient contained in the pharmaceutical dosage form The dosage is preferably 2 mg to 28 mg, more preferably 4 mg to 26 mg, even more preferably 5 mg to 24 mg, even more preferably 6 mg to 22 mg, most preferably 7 mg to 20 mg, especially 8 mg to 18 mg. mg.

In another preferred embodiment, especially when the pharmaceutical dosage form is used for the treatment of neuropathic pain and the second pharmacologically active ingredient is piroxicam, the dosage of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 1/n µg to 800/n µg or 1/n µg to 600/n µg or 1/n µg to 400/n µg or 1/n µg to 250/n µg, more preferably 5/n µg to 150/n µg, then More preferably 10/n µg to 100/n µg, most preferably 20/n µg to 80/n µg, especially 30/n µg to 50/n µg; and the second pharmacologically active ingredient contained in the pharmaceutical dosage form The dosage is preferably 5 mg to 50 mg, more preferably 7 mg to 45 mg, still more preferably 9 mg to 40 mg, still more preferably 12 mg to 35 mg, most preferably 13 mg to 30 mg, especially 15 mg to 25 mg .

In yet another preferred embodiment, especially when the pharmaceutical dosage form is used for the treatment of neuropathic pain and the second pharmacologically active ingredient is tenoxicam, the dose of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 1 /n µg to 800/n µg or 1/n µg to 600/n µg or 1/n µg to 400/n µg or 1/n µg to 250/n µg, more preferably 5/n µg to 150/n µg , more preferably 10/n µg to 100/n µg, most preferably 20/n µg to 80/n µg, especially 30/n µg to 50/n µg; and the second pharmacological activity contained in the pharmaceutical dosage form The dosage of the ingredients is preferably from 5 mg to 50 mg, more preferably from 7 mg to 45 mg, still more preferably from 9 mg to 40 mg, still more preferably from 12 mg to 35 mg, most preferably from 13 mg to 30 mg, especially from 15 mg to 25 mg.

In another preferred embodiment, especially when the pharmaceutical dosage form is used for the treatment of neuropathic pain and the second pharmacologically active ingredient is lornoxicam, the dosage of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 1 /n µg to 800/n µg or 1/n µg to 600/n µg or 1/n µg to 400/n µg or 1/n µg to 250/n µg, more preferably 5/n µg to 150/n µg , more preferably 10/n µg to 100/n µg, most preferably 20/n µg to 80/n µg, especially 30/n µg to 50/n µg; and the second pharmacological activity contained in the pharmaceutical dosage form The dosage of the ingredients is preferably from 2 mg to 26 mg, more preferably from 4 mg to 24 mg, still more preferably from 5 mg to 22 mg, still more preferably from 6 mg to 20 mg, most preferably from 7 mg to 18 mg, especially from 8 mg to 16 mg.

In another preferred embodiment, the pharmaceutical dosage form is used for the treatment of nociceptive pain, which may optionally be superimposed on neuropathic pain, wherein the dosage of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably from 50/n µg to 2,000 /n µg or 50/n µg to 1,400/n µg or 50/n µg to 1,200/n µg or 50/n µg to 1,000/n µg, more preferably 100/n µg to 800/n µg, even more preferably 150 /n µg to 650/n µg, still more preferably 250/n µg to 550/n µg, most preferably 350/n µg to 450/n µg. According to this embodiment, the dosage of the second pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 2/n mg to 50/n mg.

In yet another preferred embodiment, especially when the pharmaceutical dosage form is used to treat nociceptive pain and the second pharmacologically active ingredient is meloxicam, the dose of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 50 /n µg to 2,000/n µg or 50/n µg to 1,400/n µg or 50/n µg to 1,200/n µg or 50/n µg to 1,000/n µg, more preferably 100/n µg to 800/n µg , more preferably 150/n µg to 650/n µg, more preferably 250/n µg to 550/n µg, most preferably 350/n µg to 450/n µg; and the second pharmacological contained in the pharmaceutical dosage form The dosage of the active ingredient is preferably from 2 mg to 28 mg, more preferably from 4 mg to 26 mg, still more preferably from 5 mg to 24 mg, still more preferably from 6 mg to 22 mg, most preferably from 7 mg to 20 mg, especially 8 mg to 18 mg.

In another preferred embodiment, especially when the pharmaceutical dosage form is used for the treatment of nociceptive pain and the second pharmacologically active ingredient is piroxicam, the dosage of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 50/n µg to 2,000/n µg or 50/n µg to 1,400/n µg or 50/n µg to 1,200/n µg or 50/n µg to 1,000/n µg, more preferably 100/n µg to 800/n µg, then More preferably 150/n µg to 650/n µg, more preferably 250/n µg to 550/n µg, most preferably 350/n µg to 450/n µg; and the second pharmacologically active ingredient contained in the pharmaceutical dosage form The dosage is preferably 5 mg to 50 mg, more preferably 7 mg to 45 mg, even more preferably 9 mg to 40 mg, even more preferably 12 mg to 35 mg, most preferably 13 mg to 30 mg, especially 15 mg to 25 mg mg.

In another preferred embodiment, especially when the pharmaceutical dosage form is used to treat nociceptive pain and the second pharmacologically active ingredient is tenoxicam, the dosage of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 50 /n µg to 2,000/n µg or 50/n µg to 1,400/n µg or 50/n µg to 1,200/n µg or 50/n µg to 1,000/n µg, more preferably 100/n µg to 800/n µg , more preferably 150/n µg to 650/n µg, more preferably 250/n µg to 550/n µg, most preferably 350/n µg to 450/n µg; and the second pharmacological contained in the pharmaceutical dosage form The dosage of the active ingredient is preferably from 5 mg to 50 mg, more preferably from 7 mg to 45 mg, still more preferably from 9 mg to 40 mg, still more preferably from 12 mg to 35 mg, most preferably from 13 mg to 30 mg, especially 15 mg to 25 mg.

In yet another preferred embodiment, especially when the pharmaceutical dosage form is used to treat nociceptive pain and the second pharmacologically active ingredient is lornoxicam, the dosage of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably 50 /n µg to 2,000/n µg or 50/n µg to 1,400/n µg or 50/n µg to 1,200/n µg or 50/n µg to 1,000/n µg, more preferably 100/n µg to 800/n µg , more preferably 150/n µg to 650/n µg, more preferably 250/n µg to 550/n µg, most preferably 350/n µg to 450/n µg; and the second pharmacological contained in the pharmaceutical dosage form The dosage of the active ingredient is preferably from 2 mg to 26 mg, more preferably from 4 mg to 24 mg, still more preferably from 5 mg to 22 mg, still more preferably from 6 mg to 20 mg, most preferably from 7 mg to 18 mg, especially 8 mg to 16 mg.

The pharmaceutical composition preferably contains the first and second pharmacologically active ingredients in a weight ratio such that the first and second pharmacologically active ingredients exert a synergistic therapeutic effect when administered to a patient. Thus, the term "synergistic effect" refers to a synergistic effect on the prevention or treatment of pain (synergistic analgesic effect). The appropriate weight ratio of the pharmacologically active ingredients to produce a synergistic therapeutic effect can be determined by methods well known to those skilled in the art.

Another aspect of the present invention relates to a method of treating or preventing pain comprising administering, preferably orally, a pharmaceutical dosage form of the present invention to a subject in need thereof, preferably twice daily or once daily.

In a particularly preferred embodiment,

- the first pharmacologically active ingredient is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro according to formula (I) in its free base form - 3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine or its hemicitrate, hydrochloride or maleate; and /or

- the second pharmacologically active ingredient is an oxicam selected from the group consisting of meloxicam, piroxicam, tenoxicam, lornoxicam and their physiologically acceptable salts; and/or

- the pharmaceutical composition and the pharmaceutical dosage form contain the first pharmacologically active ingredient in a dose of 20 μg to 80 μg or 80 μg to 200 μg or 200 μg to 800 μg or 800 μg to 1,200 μg, respectively; and/or

- the pharmaceutical composition and the pharmaceutical dosage form each contain a second pharmacologically active ingredient in a dose of 2 mg to 50 mg; and/or

- in the pharmaceutical composition and the pharmaceutical dosage form, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is in the range of 1:2 to 1:1,000,000, preferably 1:2 to 1:10,000; and/or

- the pharmaceutical composition for the prevention or treatment of pain; and/or

- the pharmaceutical composition is for the treatment of pain, wherein the pain is peripheral, central or musculoskeletal pain; and/or acute, subacute or chronic pain; and/or moderate to severe pain; and/or neuropathic or psychopathic or nociceptive or mixed pain; and/or low back pain, visceral pain, or headache; and/or postoperative pain, cancer pain, or inflammatory pain; and/or

- the pharmaceutical composition and the pharmaceutical dosage form respectively contain the first pharmacologically active ingredient and the second pharmacologically active ingredient in a weight ratio such that the first pharmacologically active ingredient and the second pharmacologically active ingredient exert a synergistic effect when administered to a patient; and/or

- the pharmaceutical dosage form provides immediate in vitro release of the first pharmacologically active ingredient according to Ph. Eur.; and/or

- the pharmaceutical dosage form provides in vitro immediate or controlled release of the second pharmacologically active ingredient according to Ph. Eur.; and/or

- the pharmaceutical dosage form is administered orally; and/or

- The pharmaceutical dosage form is administered less frequently than once daily, in particular every other day or once, twice or three times daily.

In another aspect, the invention relates to a kit comprising a first pharmaceutical dosage form comprising a first pharmacologically active ingredient as described above and a second pharmaceutical dosage form comprising a second pharmacologically active ingredient as described above.

A suitable embodiment is a kit wherein a first pharmaceutical dosage form comprising a first pharmacologically active ingredient and a second pharmaceutical dosage form comprising a second pharmacologically active ingredient, although spatially separated, are in a common presentation form, e.g. a packaging supply.

The first and second pharmaceutical dosage forms are preferably suitable for simultaneous or sequential administration, wherein the first pharmaceutical dosage form may be administered before or after the second pharmaceutical dosage form and wherein the first and second pharmaceutical dosage forms are administered by the same or different routes of administration .

For purposes of the specification, the term "simultaneous administration" preferably means that the first and second pharmaceutical dosage forms are administered within a time span of 15 minutes of each other, while the term "sequential administration" preferably means that the first and second pharmaceutical dosage forms are administered within 15 minutes of each other. Dosing within more than 15 minutes of each other.

In a preferred embodiment, the first and second pharmaceutical dosage forms are suitable for administration to the patient by the same route.

In another preferred embodiment, the first and second pharmaceutical dosage forms are suitable for administration to the patient by different routes.

In a preferred embodiment, the first and second pharmaceutical dosage forms are administered simultaneously.

In another preferred embodiment, the first and second pharmaceutical dosage forms are administered sequentially.

In a preferred embodiment, the first and/or second pharmaceutical dosage form is adapted to be administered less frequently than once daily.

In another preferred embodiment, the first and/or the second pharmaceutical dosage form is suitable for once-daily administration.

In a further preferred embodiment, the first and/or the second pharmaceutical dosage form is suitable for multiple daily administrations, in particular twice daily or thrice daily.

In a preferred embodiment, the first pharmaceutical dosage form is suitable for once-daily administration and the second pharmaceutical dosage form is suitable for multiple, in particular twice-daily or thrice-daily administration.

In another preferred embodiment, the first pharmaceutical dosage form is suitable for multiple daily administration, in particular twice daily administration, and the second pharmaceutical dosage form is suitable for once daily administration.

Suitable routes of administration for the pharmaceutical dosage forms contained in the kit include, but are not limited to, oral, intravenous, intraperitoneal, intradermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous and/or rectal administration.

In a preferred embodiment, one or both of the pharmaceutical dosage forms contained in the kit are for oral administration.

In another preferred embodiment, one or both of the pharmaceutical dosage forms contained in the kit are intended for parenteral, in particular intravenous, intraperitoneal, intrathecal, intramuscular or subcutaneous administration.

In yet another preferred embodiment, one or both of the pharmaceutical dosage forms contained in the kit are for rectal administration.

In a preferred embodiment, the first and the second pharmaceutical dosage form are for oral simultaneous administration less frequently than once daily, in particular once every other day.

In another preferred embodiment, the first and second pharmaceutical dosage forms are for once-daily oral administration simultaneously.

In yet another preferred embodiment, the first and second pharmaceutical dosage forms are for multiple daily, twice daily or thrice daily oral simultaneous administration.

In yet another preferred embodiment, the first and second pharmaceutical dosage forms are each for once-daily oral sequential administration.

In another preferred embodiment, the first and second pharmaceutical dosage forms are for each once-daily sequential administration, wherein the first and second pharmaceutical dosage forms are suitable for administration by different routes, such as oral and parenteral or rectal administration.

In another preferred embodiment, the first and the second pharmaceutical dosage form are each intended for oral sequential administration less frequently than once a day, in particular every other day.

In a further preferred embodiment, the first and the second pharmaceutical dosage form are each intended for multiple daily, in particular twice daily or thrice daily oral sequential administration.

In another preferred embodiment, the first and second pharmaceutical dosage forms are each intended for multiple daily, in particular twice daily or thrice daily sequential administration, wherein the first and second pharmaceutical dosage forms are suitable for administration by different routes. medicines, such as oral and parenteral or rectal.

The following examples further illustrate the invention but should not be construed as limiting its scope.

pharmacological method

Hereinafter, the first pharmacologically active ingredient (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane -1,1'-pyrano[3,4,b]indol]-4-amine was used as hemi-citrate. Therefore, all amounts of the first pharmacologically active ingredient are prescribed as hemi-citrate.

As the second pharmacologically active ingredient, meloxicam was used.

Example 1: Paw incision model in rats (postoperative pain)

Experiments were performed in male albino mice (Sprague Dawley) weighing 170-230 g from a commercial breeder (Janvier; France). Animals were housed under standard conditions: light/dark cycle (06.00h-18.00h light, 18.00h-06.00h dark); room temperature 20°C - 24°C; relative air humidity 35% - 70%; 15 air changes per hour , air flow <0.2 m/sec. Animals received tap water and a standard laboratory chow diet (Ssniff R/M-Haltung, Ssniff Spezialdiäten GmbH, Soest, Germany) ad libitum. Both were withdrawn during the trial. All rats were used only once. Ten rats were used in each experimental group. There was at least 5 days between animal delivery and the day of surgery.

Rats are housed in wire-bottomed plastic cages that allow full access to the paws. Hind paw withdrawal threshold after mechanical stimulation was tested with electronic Von Frey cilia (SomedicSales AB, Hörby, Sweden). Animals were placed in wire-bottomed plastic cages that allowed full access to the paws. Allow behavioral adaptation for 30 min. In each case, the paw withdrawal response was measured in the area adjacent to the wound (ipsilateral) and in the same area on the uninjured foot (contralateral). Two hours after surgery, primary hypersensitivity was tested as tactile paw withdrawal threshold shortly before dosing and at various time points after dosing. Vehicle-injected animals served as controls. Pre-trial measurements were performed before surgery, two thresholds were acquired per trial and the mean value was calculated.

Surgery was performed as described above (Brennan T.J., Vandermeulen E.P. and Gebhart G.F., Characterization of a rat model of incisional pain, Pain 1996; 64:493-501).

Briefly, rats were anesthetized with isoflurane and a 1 cm incision was made longitudinally through the skin and fascia on the plantar surface, starting at the proximal edge of the heel and extending toward the metatarsal. Lift the plantaris and cut longitudinally. The muscle origin and insertion remain intact. After spreading the muscle and applying gentle pressure to stop the bleeding, the skin is closed with two individual interrupted sutures. Following surgery, rats were awakened in their home cages and animals regained consciousness within 2 to 5 minutes. To ensure full recovery from anesthesia, baseline values for individual animals were not recorded until 2 hours after surgery.

The first pharmacologically active ingredient was dissolved in 5% DMSO and 95% glucose solution (5%). The second pharmacologically active ingredient was dissolved in 1% CMC in distilled water. Administered intravenously (i.v.) and intraperitoneally (i.p.) in a volume of 5 ml/kg.

Data were recorded and median values were calculated from the 5 values measured for each animal.

The median value for each latency period was calculated as a percentage of maximum possible effect (%MPE) according to the following formula:

%MPE = 100 - [(value after administration - preliminary test before operation)/(preliminary test after operation - preliminary test before operation) · 100].

Individual %MPE values were averaged across treatment groups and expressed as mean %MPE ± standard error of the mean (SEM).

The pharmacologically active ingredients are administered using a logarithmic staggered dosage regimen. Results are presented in the graph as mean ± SEM of control postoperative time.

Data were analyzed with the aid of two-way analysis of variance (ANOVA) under repeated measures. The significance of treatment-, time-, or treatment x time interaction effects was analyzed with the help of Wilks' Lambda statistics. In the case of significant treatment effects, pairwise comparisons at different time points were performed by Fisher's least significant difference test. Results were considered statistically significant if p < 0.05.

_ED50 values were determined by regression analysis in case of dose-dependent results (according to Litchfield JT and Wilcoxon FA, A simplified method of evaluating dose-effect experiments, J. Pharmacol. Exp. Ther. 1949; 96: 99-113). The first and second pharmacological activity according to the invention are carried out by statistical comparison of the theoretical additive _ED50 values or by comparison of the theoretical additive effect of defined doses of the first and second pharmacologically active ingredients with the experimentally determined effect of their combination Analysis of results of superadditive effects of components. If the ED ₅₀ can be calculated, a statistical comparison of the theoretical ED ₅₀ of the so-called fixed ratio combination with the experimentally determined ED ₅₀ is performed (according to Tallarida JT, Porreca F. and Cowan A., Statistical analysis of drug-drug and site-siteinteractions with isobolograms, Life Sci. 1989; 45: 947-961).

Interaction studies provided herein are performed by comparing the theoretical additive effects of defined doses of the first and second pharmacologically active ingredients with the experimentally determined effects of their combination.

The route of administration is intravenous administration (i.v.) of the first pharmacologically active ingredient and intraperitoneal administration (i.p.) of the second pharmacologically active ingredient.

The test was carried out using a dose of 0.0046 mg/kg body weight to 0.010 mg/kg body weight of the first pharmacologically active ingredient and a dose of 21.5 mg/kg body weight of the second pharmacologically active ingredient.

The first and second pharmacologically active ingredients are administered simultaneously.

In the case of the combined administration according to the invention of the first and the second pharmacologically active ingredient, the time point for the potency calculation corresponds to the time point of the peak effect of the respective pharmacologically active ingredient. The effects of experiments using fixed dose combinations showed experimentally determined potencies higher than theoretically calculated potencies. Thus, this combination study demonstrates a significant synergistic interaction of the first pharmacologically active ingredient with the second pharmacologically active ingredient.

When administered in combination, the first and second pharmacologically active ingredients exhibit dose-dependent analgesic efficacy. Co-administration of the first pharmacologically active ingredient (0.010 mg/kg body weight i.v.) and the second pharmacologically active ingredient (21.5 mg/kg body weight i.p.) at a dose ratio of 1:2,150 produced an MPE of 82% at 30 minutes post-dose maximum effect.

This analysis revealed a significant synergistic interaction of the first pharmacologically active ingredient (0.010 mg/kg bw iv) and the second pharmacologically active ingredient (21.5 mg/kg bw ip) with an _ED50 value of 21.506 (21.506 – 21.507) mg/kgi. p./iv.

Adverse effects (sedation) occur when the first pharmacologically active ingredient is co-administered at a dose of 0.010 mg/kg body weight i.v. and with a dose of 21.5 mg/kg body weight i.p. of the second pharmacologically active ingredient.

Figure 1 shows the paw withdrawal threshold in g as a function of the time elapsed after dosing.

Figure 2 shows the % MPE (Maximum Probable Effect) of the first and second pharmacologically active ingredients and the combined administration of the first and second pharmacologically active ingredients and Theoretical % MPE for co-administration.

Figure 3 shows the % MPE (maximum probable effect) of the first and second pharmacologically active ingredients and the combined administration of the first and second pharmacologically active ingredients and the first and second pharmacologically active ingredients as a function of time after administration. Theoretical % MPE for co-administration.

Figure 4 shows the % MPE (Maximum Probable Effect) of the first and second pharmacologically active ingredients and the combined administration of the first and second pharmacologically active ingredients and Theoretical % MPE for co-administration.

The results of the isobolometric analysis are summarized in Tables 1 to 7 below.

Table 1: Data corresponding to Figure 1

Analysis of the % MPE (Maximum Probable Effect) of the co-administration of the first and second pharmacologically active ingredients as a function of time after administration and the interaction between the first and second pharmacologically active ingredients:

p: Statistical significance level.

Table 2: Data corresponding to Figure 1

% MPE : GLM repeated measures and statistical evaluation of data according to two-way analysis of variance (ANOVA) and Fisher's LSD:

p: Statistical significance level.

Table 3: Data corresponding to Figure 1

Ipsilateral : GLM repeated measures and statistical evaluation of data according to two-way analysis of variance (ANOVA) and Fisher's LSD:

p: Statistical significance level.

Table 4: Data corresponding to Figure 1

Contraside: GLM repeated measures and statistical evaluation of data according to two-way analysis of variance (ANOVA) and Fisher's LSD:

p: Statistical significance level.

Table 5: Data corresponding to Figure 2

% MPE (maximum probable effect) of the first and second pharmacologically active ingredients and the combination of the first and second pharmacologically active ingredients and the combination of the first and second pharmacologically active ingredients as a function of time after administration Theoretical % MPE and analysis of the interaction between the first and second pharmacologically active ingredients:

p: statistical significance level

*: Experimental value of co-administration vs. theoretical additive value of co-administration.

Table 6: Data corresponding to Figure 3

% MPE (maximum probable effect) of the first and second pharmacologically active ingredients and the combination of the first and second pharmacologically active ingredients and the combination of the first and second pharmacologically active ingredients as a function of time after administration Theoretical % MPE and analysis of the interaction between the first and second pharmacologically active ingredients:

p: statistical significance level

*: Experimental value of co-administration vs. theoretical additive value of co-administration.

Table 7: Data corresponding to Figure 4

% MPE (maximum probable effect) of the first and second pharmacologically active ingredients and the combination of the first and second pharmacologically active ingredients and the combination of the first and second pharmacologically active ingredients as a function of time after administration Theoretical % MPE and analysis of the interaction between the first and second pharmacologically active ingredients:

p: statistical significance level

*: Experimental value of co-administration vs. theoretical additive value of co-administration.

Example 2: Randall Selitto Test in Rats

Pharmacodyn., 1957, 111: 409-419 can be determined by Randall and Selitto's test (which is a model of inflammatory pain) as described in Arch. Int. The weight ratio of the two pharmacologically active ingredients. The corresponding parts of this document are hereby incorporated by reference and constitute part of the present disclosure.

Edema was induced by injecting 0.1 ml of a carrageenan suspension ventrally into the rat's hind paw, on which pain was induced after 4 hours by continuously increasing pressure with a stamp (2 mm tip diameter). The antinociceptive and antihyperalgesic activities of the tested pharmacologically active ingredients were determined at different time points after administration of the pharmacologically active ingredients. The measurement to be determined and which is also the endpoint of the pain test is the pressure at which the rat produces a vocalization response. Calculate the percent maximum possible effect (%MPE). The stamp has a maximum pressure of 250 g. The number of group members is n = 12.

_ED50 values were determined by regression analysis in case of dose-dependent results (according to Litchfield JT and Wilcoxon FA, A simplified method of evaluating dose-effect experiments, J. Pharmacol. Exp. Ther. 1949; 96: 99-113). The analysis of the results of the superadditive effect of the first and second pharmacologically active ingredients is carried out by statistical comparison of the theoretical additive _ED50 values of the so-called fixed ratio combinations with the experimentally determined _ED50 values (according to Tallarida JT, Porreca F. and Cowan A ., Statistical analysis of drug-drug and site-site interactions with isobolograms, Life Sci. 1989; 45: 947-961).

Interaction studies provided herein are performed using equivalent doses of the first and second pharmacologically active ingredients calculated from the ratio of their respective _ED50 values when administered alone.

The route of administration is intravenous administration (i.v.) of the first pharmacologically active ingredient and intraperitoneal administration (i.p.) of the second pharmacologically active ingredient. The first pharmacologically active ingredient was dissolved in 5% DMSO, 5% Cremophor and 90% glucose solution (5%). The second pharmacologically active ingredient was dissolved in 1% CMC in distilled water. Intravenous (i.v.) and intraperitoneal (i.p.) administration was performed at a volume of 5 ml/kg.

In the case of combined simultaneous administration, the relative dose ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is 1:42,549.

When the first pharmacologically active ingredient—(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H in the form of hemi-citrate - Spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine, when administered alone, had a peak effect at 15 minutes after dosing (time of first measurement points), corresponding to an ED ₅₀ value of 3.31 (3.06 – 3.56) µg/kg iv. The second pharmacologically active ingredient, meloxicam, induced a dose-dependent analgesic effect with an ED ₅₀ value of 140,862 (118,952 – 166,964) µg/kg ip, reaching the peak effect at 180 minutes after administration. According to their respective peak effect time points, the first pharmacologically active ingredient was administered 15 minutes before the measurement time point of the interaction experiment, and the second pharmacologically active ingredient was administered 180 minutes before the measurement time point of the interaction experiment (i.e., the second The pharmacologically active ingredient was administered 165 minutes before the first pharmacologically active ingredient).

Thus, the time point at which the _ED50 is calculated in the case of the combined administration according to the invention of the first and the second pharmacologically active ingredient corresponds to the time point of the peak effect of the respective pharmacologically active ingredient. Isobolometric analysis revealed that the experimental _ED50 values of the combined administration of the first and second pharmacologically active ingredients were significantly lower than the respective theoretical _ED50 values. Thus, this combination study demonstrates a significant synergistic interaction of the first pharmacologically active ingredient with the second pharmacologically active ingredient.

The results of the isobolometric analysis are summarized in Table 8 below.

Figure 5 shows the experimental ED50 values corresponding to the administration of the first pharmacologically active ingredient and meloxicam as the second pharmacologically active ingredient, respectively, and the experimental _ED50 values compared with the experimental _ED50 values measured for the combination of the first and second pharmacologically active ingredients. Graphical analysis of the corresponding theoretical additive values for co-administration of second pharmacologically active ingredients.

Table 8:

Experimental _ED50 values of the first and second pharmacologically active ingredients and isobolometric analysis of the interaction between the first and second pharmacologically active ingredients:

p: Statistical significance level.

Claims (15)

1. A pharmaceutical composition comprising: a) a first pharmacologically active ingredient selected from (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[ Cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine and physiologically acceptable salts thereof, and b) A second pharmacologically active ingredient which is an oxicam selected from the group consisting of meloxicam, piroxicam, tenoxicam, lornoxicam, droxicam and physiologically acceptable salts thereof. 2. The pharmaceutical composition according to claim 1, wherein the first pharmacologically active ingredient is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole]-4-amine. 3. The pharmaceutical composition according to claim 1 or 2, wherein the second pharmacologically active ingredient is an oxicam selected from meloxicam, piroxicam, tenoxicam, lornoxicam and physiologically acceptable salts thereof Health category. 4. The pharmaceutical composition according to any one of the preceding claims, comprising said first and second pharmacologically active ingredients in a weight ratio such that said first and second pharmacologically active ingredients exert a synergistic effect when administered to a patient . 5. The pharmaceutical composition according to any one of the preceding claims, wherein the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is in the range of 1:2 to 1:10,000. 6. A pharmaceutical composition according to any one of the preceding claims for use in the prevention or treatment of pain. 7. The pharmaceutical composition according to claim 6, wherein said pain is: - Peripheral, central, or musculoskeletal pain; and/or - Acute, subacute or chronic pain; and/or - Moderate to severe pain; and/or - neuropathic or psychiatric or nociceptive or mixed pain; and/or - low back pain, visceral pain or headache; and/or - Postoperative pain, cancer pain or inflammatory pain. 8. A pharmaceutical dosage form comprising a pharmaceutical composition according to any one of the preceding claims. 9. The pharmaceutical dosage form according to claim 8, which contains said first pharmacologically active ingredient in a dose of 10 to 1,200 micrograms. 10. Pharmaceutical dosage form according to claim 8 or 9, which contains the second pharmacologically active ingredient in a dose of 2 to 50 mg. 11. The pharmaceutical dosage form according to any one of claims 8 to 10, wherein the dose of the first pharmacologically active ingredient is in the range of 1:20 to 20:1 of an amount equivalent to the dose of the second pharmacologically active ingredient within range. 12. The pharmaceutical dosage form according to any one of claims 8 to 11, for oral, intravenous, intraperitoneal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous or rectal administration. 13. The pharmaceutical dosage form according to any one of claims 8 to 12, which provides an immediate or controlled release of the first pharmacologically active ingredient and/or the second pharmacologically active ingredient under in vitro conditions. 14. A kit comprising a first pharmaceutical dosage form comprising a first pharmacologically active ingredient as claimed in claim 1 or 2 and a second pharmaceutical dosage form comprising a second pharmacologically active ingredient as claimed in claim 1 or 3 . 15. The kit according to claim 14, wherein said first and second pharmaceutical dosage forms are suitable for simultaneous or sequential administration by the same or different routes of administration.